Ocular therapy using glucocorticoid derivatives selectively penetrating posterior segment tissues

ABSTRACT

Ophthalmically therapeutic materials, such as liquid-containing compositions and polymeric drug delivery systems, include a therapeutic component that includes an Glucocorticoid Derivative which, upon delivery to the posterior segment of a mammalian eye, does not significantly diffuse to the anterior segment of said eye. Methods of making and using the present materials are also described.

CROSS REFERENCE

The present application is a divisional of Ser. No. 15/043,750, filedFeb. 15, 2016, now U.S. Pat. No. 9,820,995, which is a continuation ofU.S. patent application Ser. No. 14/463,034, filed Aug. 19, 2014, nowU.S. Pat. No. 9,259,429, which is a continuation of U.S. patentapplication Ser. No. 13/299,215, filed on Nov. 17, 2011, now U.S. Pat.No. 8,840,872, which is a divisional application of U.S. patentapplication Ser. No. 11/550,642, filed on Oct. 18, 2006, now U.S. Pat.No. 8,062,657, which claims priority to the U.S. Provisional PatentApplication Ser. No. 60/728,209, filed on Oct. 18, 2005, the entirecontents of the preceding are hereby incorporated by reference.

BACKGROUND OF THE INVENTION

The mammalian eye is a complex organ comprising an outer coveringincluding the sclera (the tough white portion of the exterior of theeye) and the cornea, the clear outer portion covering the pupil andiris. In a medial cross section, from anterior to posterior, the eyecomprises features including, without limitation: the cornea, theanterior chamber (a hollow feature filled with a watery clear fluidcalled the aqueous humor and bounded by the cornea in the front and thelens in the posterior direction), the iris (a curtain-like feature thatcan open and close in response to ambient light) the lens, the posteriorchamber (filled with a viscous fluid called the vitreous humor), theretina (the innermost coating of the back of the eye comprised oflight-sensitive neurons), the choroid (and intermediate layer providingblood vessels to the cells of the eye), and the sclera. The posteriorchamber comprises approximately ⅔ of the inner volume of the eye, whilethe anterior chamber and its associated features (lens, iris etc.)comprise about ⅓ of the eye's volume.

The delivery of therapeutic agents to the anterior surface of the eye isrelatively routinely accomplished by topical means such as eye drops.However, the delivery of such therapeutic agents to the interior or backof the eye, even the inner portions of the cornea, presents uniquechallenges. Drugs are available that may be of use in treating diseasesof the posterior segment of the eye, including pathologies of theposterior sclera, the uveal tract, the vitreous, the choroid, retina andoptic nerve head (ONH).

However, a major limiting factor in the effective use of such agents isactually getting the agent to the affected tissue. The urgency todevelop such methods can be inferred from the fact that the leadingcauses of vision impairment and blindness are posterior segment-linkeddiseases. These diseases include, without limitation, age-relatedmacular degeneration (ARMD), proliferative vitreoretinopathy (PVR),diabetic macular edema (DME), and endophthalmitis. Glaucoma, which isoften thought of as a condition of the anterior chamber affecting theflow (and thus the intraocular pressure (IOP)) of aqueous humor, alsohas a posterior segment component; indeed, certain forms of glaucoma arenot characterized by high IOP, but mainly by retinal degeneration alone.

The present invention relates to the use of Glucocorticoid Derivatives(GDs) that are either selectively designed to possess the ability to bedirected to tissue of the posterior segment of the eye, or which possessthe ability, when administered to the posterior segment of the eye, topreferentially penetrate, be taken up by, and remain within theposterior segment of the eye, as compared to the anterior segment of theeye. More specifically, the invention is drawn to ophthalmiccompositions and drug delivery systems that provide extended release ofthe Glucocorticoid Derivatives to the posterior segment (or tissuecomprising within the posterior segment) of an eye to which the agentsare administered, and to methods of making and using such compositionsand systems, for example, to treat or reduce one or more symptoms of anocular condition to improve or maintain vision of a patient.

Glucocorticoids are one of the three major classes of steroid hormones,the other two being the sex hormones and the mineralcorticoids. Thenaturally occurring glucocoricoids include cortisol (hydrocortisone),which is essential for the maintenance of life. Cortisol is a naturalligand to the glucocorticoid nuclear receptor, a member of the steroidsuperfamily of nuclear receptors, a very large family of receptors thatalso includes the retinoid receptors RAR and RXR, the peroxisomeproliferator-activated receptor (PPAR), the thyroid receptor and theandrogen receptor. Among other activities, cortisol stimulatesgluconeogenesis from amino acids and lipids, stimulates fat breakdownand inhibits glucose uptake from muscle and adipose tissue.

Glucocorticoids can therefore be distinguished by their activity, whichis associated with glucose metabolism, and by their structure. Allsteroid hormones derive their core structure from cholesterol, which hasthe following structure and numbering scheme.

Glucocorticoids are large multiringed derivatives of cholesterol; thecharacteristics comprising a hydroxyl group at C₁₁, and/or a double bondbetween C₄ and C₅. The double bond between carbons 5 & 6 is not anessential part of a glucocorticoid, nor is the identity of anyparticular R group at C₁₇.

Corticosteroids are steroid hormones released by the adrenal cortex;they comprise the mineralcorticoids (the only naturally occurringmineralcorticoid is aldosterone) and the glucocorticoids. The term“corticosteroid” is sometimes used to mean glucocorticoid, and unlessspecifically indicated otherwise, this will be the meaning in thispatent application. Exemplary glucocorticoids include, withoutlimitation, dexamethasone, betamethasone, triamcinolone, triamcinoloneacetonide, triamcinolone diacetate, triamcinolone hexacetonide,beclomethasone, dipropionate, beclomethasone dipropionate monohydrate,flumethasone pivalate, diflorasone diacetate, fluocinolone acetonide,fluorometholone, fluorometholone acetate, clobetasol propionate,desoximethasone, fluoxymesterone, fluprednisolone, hydrocortisone,hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone sodiumphosphate, hydrocortisone sodium succinate, hydrocortisone cypionate,hydrocortisone probutate, hydrocortisone valerate, cortisone acetate,paramethasone acetate, methylprednisolone, methylprednisolone acetate,methylprednisolone sodium succinate, prednisolone, prednisolone acetate,prednisolone sodium phosphate, prednisolone tebutate, clocortolonepivalate, flucinolone, dexamethasone 21-acetate, betamethasone17-valerate, isoflupredone, 9-fluorocortisone, 6-hydroxydexamethasone,dichlorisone, meclorisone, flupredidene, doxibetasol, halopredone,halometasone, clobetasone, diflucortolone, isoflupredone acetate,fluorohydroxyandrostenedione, beclomethasone, flumethasone, diflorasone,clobetasol, cortisone, paramethasone, clocortolone, prednisolone21-hemisuccinate free acid, prednisolone metasulphobenzoate,prednisolone terbutate, triamcinolone acetonide 21-palmitate,prednisolone, flurometholone, medrysone, loteprednol, fluazacort,betamethasone, prednisone, methylprednisolone, triamcinolonehexacatonide, paramethasone acetate, diflorasone, fluocinolone andfluocinonide, derivatives thereof, salts thereof, and mixtures thereof.Some of these compounds are GDs, as defined in this patent application,and others are prospective parents of such GDs.

In 1950 the Nobel Prize for Medicine was awarded to Hench, Kendall andRichenstein for their work concerning adrenal (naturally occurring) andsynthetic glucocorticoids. Since that time these compounds including,without limitation, hydrocortisone and the synthetic glucocorticoidsdexamethasone and prenisolone have been a valuable part of thephysician's arsenal of weapons to fight inflammation, inflammatorydiseases and conditions such as acute asthma.

The glucocorticoid receptor (GR) is found in almost all tissues of themammalian body. The nuclear receptors, including the glucocorticoidreceptor, are ligand-dependent transcription factors that, whenactivated, bind to chromosomal DNA and initiate or inhibit thetranscription of particular genes. As a result, steroids have myriadeffects on various systems of the body.

Historically, the short-term systemic or topical use of glucocorticoidshas been largely free of serious side effects, and the therapeuticeffects of such use are sometimes quite miraculous, particularly intreating diseases related to inflammation, such as arthritis and thelike. However, because of the diverse and somewhat poorly characterizedeffects these compounds have, prolonged use of glucocorticoids,particularly prolonged systemic exposure to these agents, can give riseto a variety of sometimes serious side effects such as glucoseintolerance, diabetes, weight gain, osteoporosis, and fatredistribution, as well as frailty and skin thinning.

The topical use of steroids in the treatment of ophthalmic conditions(particularly ocular inflammation) is also well known. Clinicians havefound topical administration of steroids to be safe and effective forshort-term use in the treatment of conditions of the anterior chamber ofthe eye. For moderate to severe inflammation loteprednol etabonate 0.5%(Lotemax®), prednisolone acetate (Pred Forte®), prednisolone sodiumphosphate (Inflamase Forte®) and rimexolone (Vexol®) have been used withsuccess, while the fluorometholones are prescribed for mild to moderateinflammation—additionally, dexamethosone and hydrocortosone are alsoused for topical ocular use. Triamcinolone (Kenalog 50®—approved fordermatological use) has been successfully used as an off-labelmedication for intravitreal injection for the treatment of macularedema.

All of the above-mentioned topical steroid preparations are designedand/or used mainly for superficial or anterior segment inflammation.However, topical application of steroid drugs does not result insignificant concentrations of the drug entering the posterior segment.Indeed, only a minute fraction of the drug topically applied to thesurface of the eye ends up within the eye, with the majority of whatdrug does enter the eye remaining contained within the anterior segment.Retisert®, is a non-biodegradable implant for delivery to the posteriorsegment. It comprises fluocinolone acetonide, and has been approved forthe treatment of chronic noninfective posterior uveitis. Retisert® hasalso been associated with 90.3% of study eyes developing cataracts,necessitating surgical removal. See Hudson, Henry L., Retinal PhysicianJuly 2005 (www.retinalphysician.com/article.aspx?article=100098),incorporated herein by reference. Some ophthalmologists have recentlymade use of the triamcinolone acetonide suspension Kenalog® 40 byinjecting into the vitreous of patients suffering from conditionsincluding, without limitation, cystic macular edema, diabetic macularedema, and wet macular degeneration. The few steroids, such asdexamethasone and triamcinolone acetonide that have been reported to beused intravitreally tend to migrate by diffusion to anterior segmenttissues, which can cause serious and unwanted side effects.

Additionally, in May 2003 Oculex Pharmaceuticals announced thatpreliminary findings from a clinical trial testing a biodegradableintravitreal implant containing 700 μg of the corticosteroiddexamethasone showed that the implant, having the trade name Posurdex®,was highly effective in improving vision in patients suffering frompersistent macular edema.

When treating conditions of the posterior segment with steroids it isparticularly preferable to reduce the exposure of anterior segmenttissues to steroids—long term use of steroids can lead to extremely highincidence of lens cataracts, ocular hypertension, and steroid-inducedglaucoma.

In part, the present invention is drawn to methods of treating a varietyof conditions of the posterior segment including (without limitation):cystic macular edema, diabetic macular edema, diabetic retinopathy,uveitis, and wet macular degeneration, by the administration of GDs,including C₁₇- and/or C₂₁-substituted GDs, to specifically target thetissue of the posterior segment of the eye, and to resist migration tothe anterior segment. In other embodiments the invention is drawn tocompositions comprising such glucocorticoid components and to methods ofadministrating such glucocorticoids.

In a particularly preferred embodiment a composition comprising one ormore GD is administered directly to the posterior segment by, forexample, injection or surgical incision. In a further embodiment thecomposition is injected directly into the vitreous humor in a fluidsolution or suspension of crystals or amorphous particles comprising aGD compound. In another embodiment the composition is comprised withinan intravitreal implant. The GD may, without limitation, be comprised ina reservoir of such implant, may be joined to a biodegradable implantmatrix in such a manner that it is released as the matrix is degraded,or may be physically blended with the biodegradable polymeric matrix.

Additionally, while less preferred, a GD of the present invention may beadministered to the posterior segment indirectly, such as (withoutlimitation) by topical ocular administration, by subconjunctival orsubscleral injection.

The GDs of the present invention all possess certain properties inaccord with the present invention. First, the GD should possess arelatively slow dissolution rate. By “relatively low dissolution rate”is mean a dissolution rate from the solid to the vitreous liquid phase,which is less than that of triamcinolone acetonide preferably 50% orless of the dissolution rate of triamcinolone acetonide, even morepreferably 25% or less than the dissolution rate of triamcinoloneacetonide, 10% or less than that of triamcinolone acetonide.

Secondly, the GD should possess a relatively low solubility in thevitreous humor. By “relatively low solubility” is mean a solubilitywhich is less than that of triamcinolone acetonide, preferably 50% orless of the dissolution rate of triamcinolone acetonide, even morepreferably 25% or less than the dissolution rate of triamcinoloneacetonide, or 10% or less than that of triamcinolone acetonide.

In another measurement of solubility, the GD used in the presentinvention has an aqueous solubility less than about 21 mg/ml, preferablyless than about 10 mg/ml, even more preferably less than about 5 mg/ml,or less than about 2 mg/ml, or less than about 1 mg/ml, or less thanabout 0.5 mg/ml or less than about 0.2 mg/ml or less than about 0.14mg/ml at room temperature and atmospheric pressure (sea level).

Finally, the GD should be highly lipophilic so as to partition well intothe membranes of retinal tissue and quickly achieve a high localconcentration of GD in retinal tissue. This means that a GD has alipophilicity (log P, where P is the octanol/water partitioncoefficient) of greater than 2.53, or greater than 3.00, or greater thanabout 3.5 or greater than about 4.00, or greater than about 4.20 at roomtemperature and atmospheric pressure (sea level).

While a most preferred GD possesses all of these properties, a GD maypossess less than all such properties so long as it possesses theproperty of remaining therapeutically active in the posterior chamberwhen delivered intravitreally, while not being present intherapeutically effective concentrations in the anterior chamber.

The vitreous chamber bathes the posterior surface of the lens and isconnected to the anterior chamber via a fluid channel that encircles thelens and continues through the pupil. Solutes (including solublizedglucocorticoids) in the vitreous may diffuse anteriorly to the lens, oraround the lens to the anterior chamber outflow apparatus (thetrabecular meshwork, Sclemm's canal), thereby causing steroid-inducedcataracts, ocular hypertension or glaucoma.

The present inventors have found that steroids that are only sparinglysoluble in vitreal fluid and that have a slow dissolution rate from thesolid to the soluble form do not migrate well to the anterior segment.While not wishing to limit the scope of the invention by theory, andonly as an illustration, the Applicants believe that the GDs of thepresent invention lack sufficient diffusional force due to their lack ofsolubility in the vitreous to move the soluble steroid through theindicated path to the anterior chamber. The lipophilicity of the GDs ofthe present invention, at the same time, encourages their partition fromthe aqueous vitreous fluid to the lipid bilayer of the retinal cellmembranes. This is thought to create a low-level intravitreal flow ofthe GD from vitreous to retina, at a concentration sufficient to providetherapeutic benefit to the retinal tissue, but at a low enough level toconfer substantially reduced exposure to the lens and anterior segmenttissues.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a view of the human eye, showing the anterior and posteriorsegments.

FIG. 2 shows scanning ocular fluorophotemetry traces of fluoresceinleakage (arbitrary fluorescence units) from rabbit retina and iris in asingle eye two days after intravitreal VEGF injection in that eye, and50 minutes after intravenous fluorescein injection (12 mg/kg).

FIG. 3 shows scanning ocular fluorophotemetry traces of fluoresceinleakage (arbitrary fluorescence units) from rabbit retina and iris in asingle eye treated with 1 mg (100 μL) crystalline dexamethasonesuspended in PBS, two days after intravitreal VEGF injection in thateye, and 50 minutes after intravenous fluorescein injection (12 mg/kg).The results indicate that intravitreally-administered dexamethasone ispresent in both posterior and anterior segments to inhibit BRB and BABbreakdown, respectively.

FIG. 4 shows scanning ocular fluorophotemetry traces of fluoresceinleakage (arbitrary fluorescence units) from rabbit retina and iris in asingle eye treated with 1 mg of triamcinolone acetonide contained in 100μL of an aqueous suspension and injected into the vitreous under thesame conditions described for FIG. 3. This also completely inhibitedVEGF-stimulated BRB and BAB breakdown.

FIG. 5 shows scanning ocular fluorophotemetry traces of fluoresceinleakage (arbitrary fluorescence units) from rabbit retina and iris in asingle eye treated with 100 μl (1 mg) of an aqueous suspension ofbeclomethasone was injected into the vitreous of a rabbit eye, followedby VEGF as described above. As with dexamethasone and triamcinolone,beclomethasone inhibited the VEGF-induced BRB and BAB breakdown.

FIG. 6 shows scanning ocular fluorophotemetry traces of fluoresceinleakage in rabbit eye injected with VEGF, and indicates that 1 mg (100μl) fluticasone propionate followed by intravitreal administration ofVEGF, completely blocks BRB breakdown but has no effect on BABbreakdown.

FIG. 7 shows scanning ocular fluorophotemetry traces of fluoresceinleakage in rabbit eye injected with VEGF, and indicates that 1 mg (100μl) beclomethasone 17,21-dipropionate followed by intravitrealadministration of VEGF, completely blocks BRB breakdown but has noeffect on BAB breakdown.

DETAILED DESCRIPTION

The GDs of the present materials refer to agents that bind or interactwith and activate the glucocorticoid receptor. Preferably, the agentsbind or interact with the GR to a greater extent than to themineralcorticoid receptor, even more preferably to an extent at leasttwice as great, or at least 5 times as great, or at least 10 times asgreat, or at least 50 times as great, or at least 100 times as great orat least 1000 times as great as the mineralcorticoid receptor. The GDsof the therapeutic component have a greater vitreous humor/aqueous humorconcentration ratio and greater vitreal half-life than other steroidsidentically administered, such as dexamethasone and triamcinoloneacetonide.

Posteriorly-directed GDs can be screened, for example, by injecting thepotential GD into a rabbit vitreous. The vitreous humor and aqueoushumor can be sampled as a function of time, and the amount of thepotential GD in the vitreous and aqueous humor can be measured. Thevitreous concentration of the potential GD can be plotted as a functionof time, and using standard pharmacokinetic techniques, the vitreoushalf-life for the GD and clearance of the potential GD can becalculated.

Similarly, the aqueous concentration of the GD can be plotted as afunction of time, and standard pharmacokinetic techniques can be used todetermine the anterior clearance of the potential GD. Agents withdesired vitreal half-lives and/or that are selectively present in thevitreous humor rather than the aqueous humor are used in the presentmaterials. For example, agents that have vitreous half-lives greaterthan about three hours can be selected for the present ophthalmicallytherapeutic materials.

Pathological Conditions of the Posterior Segment

In part, the present invention is generally drawn to methods fortreating the posterior segment of the eye. Preferably, the posteriorsegment of the eye comprises, without limitation, the uveal tract,vitreous, retina, choroid, optic nerve, and the retinal pigmentedepithelium (RPE). The disease or condition related to this invention maycomprise any disease or condition that can be prevented or treated bythe action of a glucocorticoid, especially a GD, upon a posterior partof the eye. While not intending to limit the scope of this invention inany way, some examples of diseases or conditions that can be preventedor treated by the action of an active drug upon the posterior part ofthe eye in accordance with the present invention may includemaculopathies/retinal degeneration such as macular edema, anterioruveitis, retinal vein occlusion, non-exudative age related maculardegeneration, exudative age related macular degeneration (ARMD),choroidal neovascularization, diabetic retinopathy, acute macularneuroretinopathy, central serous chorioretinopathy, cystoid macularedema, and diabetic macular edema; uveitis/retinitis/choroiditis such asacute multifocal placoid pigment epitheliopathy, Behcet's disease,birdshot retinochoroidopathy, infections (syphilis, lyme, tuberculosis,toxoplasmosis), intermediate uveitis (pars planitis), multifocalchoroiditis, multiple evanescent white dot syndrome (mewds), ocularsarcoidosis, posterior scleritis, serpiginous choroiditis, subretinalfibrosis and uveitis syndrome, Vogt-Koyanagi- and Harada syndrome;vascular diseases/exudative diseases such as retinal arterial occlusivedisease, central retinal vein occlusion, disseminated intravascularcoagulopathy, branch retinal vein occlusion, hypertensive funduschanges, ocular ischemic syndrome, retinal arterial microaneurysms,Coat's disease, parafoveal telangiectasis, hemiretinal vein occlusion,papillophlebitis, central retinal artery occlusion, branch retinalartery occlusion, carotid artery disease (CAD), frosted branch angiitis,sickle cell retinopathy and other hemoglobinopathies, angioid streaks,familial exudative vitreoretinopathy, and Eales disease;traumatic/surgical conditions such as sympathetic ophthalmia, uveiticretinal disease, retinal detachment, trauma, conditions caused by laser,conditions caused by photodynamic therapy, photocoagulation,hypoperfusion during surgery, radiation retinopathy, and bone marrowtransplant retinopathy; proliferative disorders such as proliferativevitreal retinopathy and epiretinal membranes, and proliferative diabeticretinopathy; infectious disorders such as ocular histoplasmosis, oculartoxocariasis, presumed ocular histoplasmosis syndrome (POHS),endophthalmitis, toxoplasmosis, retinal diseases associated with HIVinfection, choroidal disease associate with HIV infection, uveiticdisease associate with HIV infection, viral retinitis, acute retinalnecrosis, progressive outer retinal necrosis, fungal retinal diseases,ocular syphilis, ocular tuberculosis, diffuse unilateral subacuteneuroretinitis, and myiasis; genetic disorders such as retinitispigmentosa, systemic disorders with associated retinal dystrophies,congenital stationary night blindness, cone dystrophies, Stargardt'sdisease and fundus flavimaculatus, Best's disease, pattern dystrophy ofthe retinal pigmented epithelium, X-linked retinoschisis, Sorsby'sfundus dystrophy, benign concentric maculopathy, Bietti's crystallinedystrophy, and pseudoxanthoma elasticum; retinal tears/holes such asretinal detachment, macular hole, and giant retinal tear; tumors such asretinal disease associated with tumors, congenital hypertrophy of theretinal pigmented epithelium, posterior uveal melanoma, choroidalhemangioma, choroidal osteoma, choroidal metastasis, combined hamartomaof the retina and retinal pigmented epithelium, retinoblastoma,vasoproliferative tumors of the ocular fundus, retinal astrocytoma, andintraocular lymphoid tumors; and miscellaneous other diseases affectingthe posterior part of the eye such as punctate inner choroidopathy,acute posterior multifocal placoid pigment epitheliopathy, myopicretinal degeneration, and acute retinal pigment epitheliitis.Preferably, the disease or condition is retinitis pigmentosa,proliferative vitreal retinopathy (PVR), age-related maculardegeneration (ARMD), diabetic retinopathy, diabetic macular edema,retinal detachment, retinal tear, uveitus, or cytomegalovirus retinitis.Glaucoma can also be considered a posterior ocular condition because thetherapeutic goal is to prevent the loss of or reduce the occurrence ofloss of vision due to damage to or loss of retinal cells or optic nervecells (i.e. neuroprotection).

The present materials claimed, and used in the methods claimed, hereininclude, without limitation, liquid-containing compositions (such asformulations) and polymeric drug delivery systems. The presentcompositions may be understood to include solutions, suspensions,emulsions, and the like, such as other liquid-containing compositionsused in ophthalmic therapies. Polymeric drug delivery systems comprise apolymeric component, and may be understood to include biodegradableimplants, nonbiodegradable implants, biodegradable microparticles, suchas biodegradable microspheres, and the like. The present drug deliverysystems may also be understood to encompass elements in the form oftablets, wafers, rods, sheets, and the like. The polymeric drug deliverysystems may be solid, semisolid, or viscoelastic.

As used herein, “periocular” administration refers to delivery of thetherapeutic component to a retrobulbar region, a subconjunctival region,a subtenon region, a suprachoroidal region or space, and/or anintrascleral region or space. For example, a posterior directed GD maybe associated with water, saline, a polymeric liquid or semisolidcarrier, phosphate buffer, or other ophthalmically acceptable liquidcarrier. The present liquid-containing compositions are preferably in aninjectable form. In other words, the compositions may be intraocularlyadministered, such as by intravitreal injection, using a syringe andneedle or other similar device (e.g., see U.S. Patent Publication No.2003/0060763), hereby incorporated by reference herein in its entirety,or the compositions can be periocularly administered using an injectiondevice.

Also as used herein the term a “therapeutically effective” amount orconcentration means an amount or concentration of a GD or aGD-containing composition sufficient, when applied to the posteriorsegment of the eye, to improve at least one symptom of a disease,condition or disorder affecting said posterior segment, as compared toan untreated eye.

A “biologically significant amount” means an amount of a GD or othersteroid present in the anterior segment of an eye sufficient to cause astatistically significant increase in either or both a) intraocularpressure or b) cataract formation as compared to an untreated eye.

The GD of the present methods and compositions may be present in anamount in the range of about 0.05% or less, or about 0.1% or about 0.2%or about 0.5% to about 5% or about 10% or about 20% or about 30% or more(w/v) of the composition. While the GD may be contained in solution(including, without limitation, a supersaturated solution), in apreferred embodiment the GD is present, at least in part, as crystals orparticles in a suspension.

For intravitreally administered compositions, providing relatively highconcentrations of the GD (for example, in the form of crystals) may bebeneficial in that reduced amounts of the composition may be required tobe placed or injected into the posterior segment of the eye in order toprovide the same amount or more of the therapeutic component in theposterior segment of the eye relative to other compositions.

In certain embodiments, the material further comprises a GD and anexcipient component. The excipient component may be understood toinclude solubilizing agents, viscosity inducing agents, buffer agents,tonicity agents, preservative agents, and the like.

In some embodiments of the present compositions, a solubilizing agentmay be a cyclodextrin. In other words, the present materials maycomprise a cyclodextrin component provided in an amount from about 0.1%(w/v) to about 5% (w/v) of the composition. In further embodiments, thecyclodextrin comprises up to about 10% (w/v) of certain cyclodextrins,as discussed herein. In further embodiments, the cyclodextrin comprisesup to about 60% (w/v) of certain cyclodextrins, as discussed herein. Theexcipient component of the present compositions may comprise one or moretypes of cyclodextrins or cyclodextrin derivatives, such asalpha-cyclodextrins, beta-cyclodextrins, gamma-cyclodextrins, andderivatives thereof. As understood by persons of ordinary skill in theart, cyclodextrin derivatives refer to any substituted or otherwisemodified compound that has the characteristic chemical structure of acyclodextrin sufficiently to function as a cyclodextrin, for example, toenhance the solubility and/or stability of therapeutic agents and/orreduce unwanted side effects of the therapeutic agents and/or to forminclusive complexes with the therapeutic agents.

Viscosity inducing agents of the present materials, include withoutlimitation, polymers that are effective in stabilizing the therapeuticcomponent in the composition. The viscosity-inducing component ispresent in an effective amount in increasing, advantageouslysubstantially increasing, the viscosity of the composition. Increasedviscosities of the present compositions may enhance the ability of thepresent compositions to maintain the GD, including GD-containingparticles, in substantially uniform suspension in the compositions forprolonged periods of time, for example, for at least about one week,without requiring resuspension processing. The relatively high viscosityof certain of the present compositions may also have an additionalbenefit of at least assisting the compositions to have the ability tohave an increased amount or concentration of the GD, as discussedelsewhere herein, for example, while maintaining such GD insubstantially uniform suspension for prolonged periods of time.

Direct Intraocular Administration

Preferably, the GDs of the present invention are administered directlyto the vitreous chamber of the eye, by means including administration ofa solution, suspension, or other means of carrying of crystals orparticles of the GD, or as part of an intravitreal implant, by, forexample, incision or injection.

The vitreous humor contained in the posterior chamber of the eye is aviscous aqueous substance. Injection of a fluid or suspension ofsubstantially lower viscosity into the posterior segment could thereforeresult in the presence of two phases or layers of different densitywithin the eye, which in turn can lead to either “pooling” of GDparticles or floating of the less dense solution. If the injected orinserted material contains a drug in the form of a solid (for example ascrystals, particles or an unsutured implant or reservoir), the solidmaterial will fall to the bottom of the eye and remain there until itdissolves. Additionally, a substantially different refractive indexbetween vitreous and the injected or inserted GD-containing compositionmay impair vision.

The therapeutic compositions, including the GDs described as part of thepresent invention, may be suspended in a viscous formulation having arelatively high viscosity, such as one approximating that of thevitreous humor. Such viscous formulation comprises a viscosity-inducingcomponent. The therapeutic agent of the present invention may beadministered intravitreally as, without limitation, an aqueousinjection, a suspension, an emulsion, a solution, a gel or inserted in asustained release or extended release implant, either biodegradable ornon-biodegradable.

The viscosity-inducing component preferably comprises a polymericcomponent and/or at least one viscoelastic agent, such as thosematerials that are useful in ophthalmic surgical procedures.

Examples of useful viscosity-inducing components include, but are notlimited to, hyaluronic acid, carbomers, polyacrylic acid, cellulosicderivatives, polycarbophil, polyvinylpyrrolidone, gelatin, dextrin,polysaccharides, polyacrylamide, polyvinyl alcohol, polyvinyl acetate,derivatives thereof and mixtures thereof.

The molecular weight of the viscosity-inducing components may be in arange up to about 2 million Daltons, such as of about 10,000 Daltons orless to about 2 million Daltons or more. In one particularly usefulembodiment, the molecular weight of the viscosity-inducing component isin a range of about 100,000 Daltons or about 200,000 Daltons to about 1million Daltons or about 1.5 million Daltons.

In one very useful embodiment, a viscosity-inducing component is apolymeric hyaluronate component, for example, a metal hyaluronatecomponent, preferably selected from alkali metal hyaluronates, alkalineearth metal hyaluronates and mixtures thereof, and still more preferablyselected from sodium hyaluronates, and mixtures thereof. The molecularweight of such hyaluronate component preferably is in a range of about50,000 Daltons or about 100,000 Daltons to about 1.3 million Daltons orabout 2 million Daltons.

In one embodiment, the GDs of the present invention may be comprised ina polymeric hyaluronate component in an amount in a range about 0.01% toabout 0.5% (w/v) or more. In a further useful embodiment, thehyaluronate component is present in an amount in a range of about 1% toabout 4% (w/v) of the composition. In this latter case, the very highpolymer viscosity forms a gel that slows the sedimentation rate of anysuspended drug, and prevents pooling of injected GD.

The GD of this aspect of the claimed invention may include any or allsalts, prodrugs, conjugates, or precursors of such therapeuticallyuseful GDs, including those specifically identified herein.

In certain embodiments, the compositions of the present invention maycomprise more than one therapeutic agent, so long as at least one suchtherapeutic agent is a GD having one or more of the properties describedherein as important to preventing migration of the GD into the anteriorsegment and/or penetration of the GD into tissue of the posteriorsegment, which tissue may include, without limitation, retinal tissue.In other words, a therapeutic composition of the present invention,however administered, may include a first therapeutic agent, and one ormore additional therapeutic agent, or a combination of therapeuticagents, so long as at least one of such therapeutic agents is a GD. Oneor more of the therapeutic agents in such compositions may be formed asor present in particles or crystals.

In these aspects of the present invention, the viscosity-inducingcomponent is present in an effective amount to increase, advantageouslysubstantially increase, the viscosity of the composition. Withoutwishing to limit the invention to any particular theory of operation, itis believed that increasing the viscosity of the compositions to valueswell in excess of the viscosity of water, for example, at least about100 cps at a shear rate of 0.1/second, compositions which are highlyeffective for placement, e.g., injection, into the posterior segment ofan eye of a human or animal are obtained. Along with the advantageousplacement or injectability of the these GD-containing compositions intothe posterior segment, the relatively high viscosity of the presentcompositions are believed to enhance the ability of such compositions tomaintain the therapeutic component (for example, comprisingGD-containing particles) in substantially uniform suspension in thecompositions for prolonged periods of time, and may aid in the storagestability of the composition.

Advantageously, the compositions of this aspect of the invention mayhave viscosities of at least about 10 cps or at least about 100 cps orat least about 1000 cps, more preferably at least about 10,000 cps andstill more preferably at least about 70,000 cps or more, for example upto about 200,000 cps or about 250,000 cps, or about 300,000 cps or more,at a shear rate of 0.1/second. In particular embodiments the presentcompositions not only have the relatively high viscosity noted above butalso have the ability or are structured or made up so as to beeffectively able to be placed, e.g., injected, into a posterior segmentof an eye of a human or animal, preferably through a 27 gauge needle, oreven through a 30 gauge needle.

The viscosity inducing components preferably are shear thinningcomponents such that as the viscous formulation is passed through orinjected into the posterior segment of an eye, for example, through anarrow aperture, such as 27 gauge needle, under high shear conditionsthe viscosity of the composition is substantially reduced during suchpassage. After such passage, the composition regains substantially itspre-injection viscosity so as to maintain any GD-containing particles insuspension in the eye.

Any ophthalmically acceptable viscosity-inducing component may beemployed in accordance with the GDs in the present invention. Many suchviscosity-inducing components have been proposed and/or used inophthalmic compositions used on or in the eye. The viscosity-inducingcomponent is present in an amount effective in providing the desiredviscosity to the composition. Advantageously, the viscosity-inducingcomponent is present in an amount in a range of about 0.5% or about 1.0%to about 5% or about 10% or about 20% (w/v) of the composition. Thespecific amount of the viscosity inducing component employed dependsupon a number of factors including, for example and without limitation,the specific viscosity inducing component being employed, the molecularweight of the viscosity inducing component being employed, the viscositydesired for the GD-containing composition being produced and/or used andsimilar factors.

Biocompatible Polymers

In another embodiment of the invention, the therapeutic agents(including at least one GD) may be delivered intraocularly in acomposition that comprises, consists essentially of, or consists of, atherapeutic agent comprising a GD and a biocompatible polymer suitablefor administration to the posterior segment of an eye. For example, thecomposition may, without limitation, comprise an intraocular implant ora liquid or semisolid polymer. Some intraocular implants are describedin publications including U.S. Pat. Nos. 6,726,918; 6,699,493;6,369,116; 6,331,313; 5,869,079; 5,824,072; 5,766,242; 5,632,984; and5,443,505, these and all other publications cited or mentioned hereinhereby incorporated by reference herein in their entirety, unlessexpressly indicated otherwise. These are only examples of particularpreferred implants, and others will be available to the person ofordinary skill in the art.

The polymer in combination with the GD-containing therapeutic agent maybe understood to be a polymeric component. In some embodiments, theparticles may comprise D,L-polylactide (PLA) or latex (carboxylatemodified polystyrene beads). In other embodiments the particles maycomprise materials other than D,L-polylactide (PLA) or latex(carboxylate modified polystyrene beads). In certain embodiments, thepolymer component may comprise a polysaccharide. For example, thepolymer component may comprise a mucopolysaccharide. In at least onespecific embodiment, the polymer component is hyaluronic acid.

However, in additional embodiments, and regardless of the method of GDadministration, the polymeric component may comprise any polymericmaterial useful in a body of a mammal, whether derived from a naturalsource or synthetic. Some additional examples of useful polymericmaterials for the purposes of this invention include carbohydrate basedpolymers such as methylcellulose, carboxymethylcellulose,hydroxymethylcellulose hydroxypropylcellulose, hydroxyethylcellulose,ethyl cellulose, dextrin, cyclodextrins, alginate, hyaluronic acid andchitosan, protein based polymers such as gelatin, collagen andglycolproteins, and hydroxy acid polyesters such as bioerodablepolylactide-coglycolide (PLGA), polylactic acid (PLA), polyglycolide,polyhydroxybutyric acid, polycaprolactone, polyvalerolactone,polyphosphazene, and polyorthoesters. Polymers can also be crosslinked,blended or used as copolymers in the invention. Other polymer carriersinclude albumin, polyanhydrides, polyethylene glycols, polyvinylpolyhydroxyalkyl methacrylates, pyrrolidone and polyvinyl alcohol.

Some examples of non-erodible polymers include silicone, polycarbonates,polyvinyl chlorides, polyamides, polysulfones, polyvinyl acetates,polyurethane, ethylvinyl acetate derivatives, acrylic resins,crosslinked polyvinyl alcohol and crosslinked polyvinylpyrrolidone,polystyrene and cellulose acetate derivatives.

These additional polymeric materials may be useful in a compositioncomprising the therapeutically useful GD agents disclosed herein, or foruse in any of the methods, including those involving the intravitrealadministration of such methods. For example, and without limitation, PLAor PLGA may be coupled to a GD for use in the present invention, eitheras particles in suspension or as part of an implant. This insolubleconjugate will slowly erode over time, thereby continuously releasingthe GD.

The term “biodegradable polymer” refers to a polymer or polymers whichdegrade in vivo, and wherein erosion of the polymer or polymers overtime occurs concurrent with or subsequent to release of the therapeuticGD agent. The terms “biodegradable” and “bioerodible” are equivalent andare used interchangeably herein. A biodegradable polymer may be ahomopolymer, a copolymer, or a polymer comprising more than twodifferent polymeric units.

The term “therapeutically effective amount” as used herein, refers tothe level or amount of GD agent needed to treat a condition of theposterior segment, or reduce or prevent ocular injury or damage withoutcausing significant negative or adverse side effects to the anteriorsegment of the eye.

Formulation Vehicles

Regardless of the mode of administration or form (e.g., in solution,suspension, as a topical, injectable or implantable agent), theGD-containing therapeutic compositions of the present invention will beadministered in a pharmaceutically acceptable vehicle component. Thetherapeutic agent or agents may also be combined with a pharmaceuticallyacceptable vehicle component in the manufacture of a composition. Inother words, a composition, as disclosed herein, may comprise atherapeutic component and an effective amount of a pharmaceuticallyacceptable vehicle component. In at least one embodiment, the vehiclecomponent is aqueous-based. For example, the composition may comprisewater.

In certain embodiments, the GD-containing therapeutic agent isadministered in a vehicle component, and may also include an effectiveamount of at least one of a viscosity inducing component, a resuspensioncomponent, a preservative component, a tonicity component and a buffercomponent. In some embodiments, the compositions disclosed hereininclude no added preservative component. In other embodiments, acomposition may optionally include an added preservative component. Inaddition, the composition may be included with no resuspensioncomponent.

Formulations for topical or intraocular administration of theGD-containing therapeutic agents (including, without limitation,implants or particles containing such agents) will preferably include amajor amount of liquid water. Such compositions are preferablyformulated in a sterile form, for example, prior to being used in theeye. The above-mentioned buffer component, if present in the intraocularformulations, is present in an amount effective to control the pH of thecomposition. The formulations may contain, either in addition to, orinstead of the buffer component at least one tonicity component in anamount effective to control the tonicity or osmolality of thecompositions. Indeed, the same component may serve as both a buffercomponent and a tonicity component. More preferably, the presentcompositions include both a buffer component and a tonicity component.

The buffer component and/or tonicity component, if either is present,may be chosen from those that are conventional and well known in theophthalmic art. Examples of such buffer components include, but are notlimited to, acetate buffers, citrate buffers, phosphate buffers, boratebuffers and the like and mixtures thereof. Phosphate buffers areparticularly useful. Useful tonicity components include, but are notlimited to, salts, particularly sodium chloride, potassium chloride, anyother suitable ophthalmically acceptably tonicity component and mixturesthereof. Non-ionic tonicity components may comprise polyols derived fromsugars, such as xylitol, sorbitol, mannitol, glycerol and the like.

The amount of buffer component employed preferably is sufficient tomaintain the pH of the composition in a range of about 6 to about 8,more preferably about 7 to about 7.5. The amount of tonicity componentemployed preferably is sufficient to provide an osmolality to thepresent compositions in a range of about 200 to about 400, morepreferably about 250 to about 350, mOsmol/kg respectively.Advantageously, the present compositions are substantially isotonic.

The compositions of, or used in, the present invention may include oneor more other components in amounts effective to provide one or moreuseful properties and/or benefits to the present compositions. Forexample, although the present compositions may be substantially free ofadded preservative components, in other embodiments, the presentcompositions include effective amounts of preservative components,preferably such components that are more compatible with or friendly tothe tissue in the posterior segment of the eye into which thecomposition is placed than benzyl alcohol. Examples of such preservativecomponents include, without limitation, quaternary ammoniumpreservatives such as benzalkonium chloride (“BAC” or “BAK”) andpolyoxamer; bigunanide preservatives such as polyhexamethylenebiguandide (PHMB); methyl and ethyl parabens; hexetidine; chloritecomponents, such as stabilized chlorine dioxide, metal chlorites and thelike; other ophthalmically acceptable preservatives and the like andmixtures thereof. The concentration of the preservative component, ifany, in the present compositions is a concentration effective topreserve the composition, and (depending on the nature of the particularpreservative used) is often and generally used in a range of about0.00001% to about 0.05% (w/v) or about 0.1% (w/v) of the composition.

Intravitreal delivery of therapeutic agents can be achieved by injectinga liquid-containing composition into the vitreous, or by placingpolymeric drug delivery systems, such as implants and microparticles,such as microspheres, into the vitreous. Examples of biocompatibleimplants for placement in the eye have been disclosed in a number ofpatents, such as U.S. Pat. Nos. 4,521,210; 4,853,224; 4,997,652;5,164,188; 5,443,505; 5,501,856; 5,766,242; 5,824,072; 5,869,079;6,074,661; 6,331,313; 6,369,116; and 6,699,493.

Other route of administering the GD-containing therapeutic agents of thepresent invention to the interior of the eye may include perioculardelivery of drugs to a patient. Penetration of drugs directly into theposterior segment of the eye is restricted by the blood-retinalbarriers. The blood-retinal barrier is anatomically separated into innerand outer blood barriers. Movement of solutes or drugs into the internalocular structures from the periocular space is restricted by the retinalpigment epithelium (RPE), the outer blood-retinal barrier. The cells ofthis structure are joined by zonulae oclludentae intercellularjunctions. The RPE is a tight ion transporting barrier that restrictsparacellular transport of solutes across the RPE. The permeability ofmost compounds across the blood-retinal barriers is very low. Lipophiliccompounds, however, such as chloramphenical and benzyl penicillin, canpenetrate the blood-retinal barrier achieving appreciable concentrationsin the vitreous humor after systemic administration. The lipophilicityof the compound correlates with its rate of penetration and isconsistent with passive cellular diffusion. The blood retinal barrier,however, is impermeable to polar or charged compounds in the absence ofa transport mechanism.

Structure of Exemplary GDs

The GDs of the present invention are compounds that 1) selectively bindto and activate the glucocorticoid receptor (glucocorticoids), 2) havean aqueous solubility less than that of triamcinolone acetonide (21μg/ml) and/or a lipophilicity (log P) greater than that of triamcinoloneacetonide (2.53). Log P is the lipophilicity coefficient, where P is theoctonol/water partition coefficient.

According to the present patent application, the basic steroid ringstructure is as follows

For example, the phosphate salt of the glucocorticoid dexamethosone hasthe following structure:

Similarly, the glucocorticoid triamcinolone acetonide has the structure:

The Glucocorticoid Derivatives (GDs) used in the compositions andmethods of the present invention also selectively bind to and activatethe glucocorticoid receptor, have an aqueous solubility less than thatof triamcinolone acetonide (21 μg/ml) and/or a lipophilicity (log P)greater than that of triamcinolone acetonide (2.53).

In a useful embodiment, the GDs of the present invention comprise anacyl group linked via an ester linkage to a glucocorticoid at the C₁₇position and/or the C₂₁ position (if the latter carbon atom is present).Preferably the ester is a monoester linkage. However, in anotherembodiment the ester is a diester linkage. Useful acyl groups include,without limitation, the acetyl, butyryl, valeryl, propionyl, or furoylgroups. Additional potentially useful groups would include the benzoylgroup and/or other substituted or unsubstituted cyclic or aromatic acylgroups. Ideally, the acyl group(s) should have high hydrophobicity; thusalkyl or aromatic acyl groups are particularly preferred in the presentapplication, while those containing polar substituents are lesspreferred, and in some embodiments of the invention are absent. Incertain of the embodiments of the present invention acyl group is linkedto the steroid by a thiol ester.

Certain C₁₇ and/or C₂₁ acyl ester-substituted glucocorticoids are usedfor treatment of inflammatory and other conditions by routes including,without limitation, such as topical skin or systemic administration. Forexample, beclomethasone dipropionate is used in the treatment ofbronchial asthma and to shrink nasal polyps. It is formulated in apowder form, and is administered by inhalation. It has the followingstructure:

While beclomethasone dipropionate is sometimes called simply“beclomethasone”, this is an incorrect use of the chemical nomenclature.Unsubstituted beclomethasone has the following structure:

Another compound comprises fluticasone propionate, having the followingstructure:

Relative to a “parent” glucocorticoid lacking hydrophobicsubstitutions(for example, an identical compound lacking the indicatedsubstitutions of a hydrophoblic (preferably acyl ester) group atpositions C₁₇ and/or C₂₁), the addition of such substitutions inaccordance with the present invention tends to result in a decreasedsolubility in aqueous medium and increased lipophilicity coefficient(log P, where P is the octanol/water partition coefficient), and slowthe compound's dissolution rate from the crystal to the solublizedphase. These physiochemical attributes experimentally reduce the amountof compound migrating from the posterior segment to the anteriorsegment, thereby resulting in reduced anterior-segment related sideeffects. At the same time, these compounds are better able to migrateinto the tissues of the posterior segment, such as the retina, the RPE,etc.), thereby selectively being directed to such tissue. When the GDsare administered to the vitreous in crystalline or particulate form, theGDs possess an extended duration of action with intravitreal deliverycompared to the parent glucocorticoid.

A non-exclusive list of currently preferred GDs includes, withoutlimitation, dexamethasone 17-acetate, dexamethasone 17, 21-acetate,dexamethasone 21-acetate, clobetasone 17-butyrate, beclomethasone 17,21-dipropionate, fluticasone 17-propionate, clobetasol 17-propionate,betamethasone 17, 21-dipropionate, alclometasone 17,21-dipropionate,dexamethasone 17,21-dipropionate, dexamethasone 17-propionate,halobetasol 17-propionate, and betamethasone 17-valerate. The use ofthese compounds for treatment of conditions of the posterior segment ofthe eye, particularly by ocular administration, such as intravitreal,subconjunctival, subscleral or topical ocular administration will confera significant therapeutic improvement compared to existing therapies inthe treatment of posterior eye diseases such as those listed above,which include, without limitation, dry and wet ARMD, diabetic macularedema, proliferate diabetic retinopathy, uveitis, and ocular tumors.

If desired, buffering agents may be provided in an amount effective tocontrol the pH of the composition. Tonicity agents may be provided in anamount effective to control the tonicity or osmolality of thecompositions. Certain of the present compositions include both a buffercomponent and a tonicity component, which may include one or more sugaralcohols, such as mannitol, or salts, such as sodium chloride, asdiscussed herein. The buffer component and tonicity component may bechosen from those that are conventional and well known in the ophthalmicart. Examples of such buffer components include, but are not limited to,acetate buffers, citrate buffers, phosphate buffers, borate buffers andthe like and mixtures thereof. Phosphate buffers are particularlyuseful. Useful tonicity components include, but are not limited to,salts, particularly sodium chloride, potassium chloride, any othersuitable ophthalmically acceptably tonicity component and mixturesthereof.

The amount of buffer component employed preferably is sufficient tomaintain the pH of the composition in a range of about 6 to about 8,more preferably about 7 to about 7.5. The amount of tonicity componentemployed preferably is sufficient to provide an osmolality to thepresent compositions in a range of about 200 to about 400, morepreferably about 250 to about 350, mOsmol/kg respectively.Advantageously, the present compositions are substantially isotonic.

Preservative agents that may be used in the present materials includebenzyl alcohol, benzalkonium chloride, methyl and ethyl parabens,hexetidine, chlorite components, such as stabilized chlorine dioxide,metal chlorites and the like, other ophthalmically acceptablepreservatives and the like and mixtures thereof. The concentration ofthe preservative component, if any, in the present compositions is aconcentration effective to preserve the composition, and is often in arange of about 0.00001% to about 0.05% or about 0.1% (w/v) of thecomposition.

The present compositions can be produced using conventional techniquesroutinely known by persons of ordinary skill in the art. For example, aGD-containing therapeutic component can be combined with a liquidcarrier. The composition can be sterilized. In certain embodiments, suchas preservative-free embodiments, the compositions can be sterilized andpackaged in single-dose amounts. The compositions may be prepackaged inintraocular dispensers which can be disposed of after a singleadministration of the unit dose of the compositions.

The present compositions can be prepared using suitableblending/processing techniques, for example, one or more conventionalblending techniques. The preparation processing should be chosen toprovide the present compositions in forms which are useful forintravitreal or periocular placement or injection into eyes of humans oranimals. In one useful embodiment a concentrated therapeutic componentdispersion is made by combining the GD-containing therapeutic componentwith water, and the excipients (other than the viscosity inducingcomponent) to be included in the final composition. The ingredients aremixed to disperse the therapeutic component and then autoclaved. Theviscosity inducing component may be purchased sterile or sterilized byconventional processing, for example, by filtering a dilute solutionfollowed by lyophylization to yield a sterile powder. The sterileviscosity inducing component is combined with water to make an aqueousconcentrate. The concentrated therapeutic component dispersion is mixedand added as a slurry to the viscosity inducing component concentrate.Water is added in a quantity sufficient (q.s.) to provide the desiredcomposition and the composition is mixed until homogenous.

In one embodiment, a sterile, viscous suspension suitable foradministration is made using an GD. A process for producing such acomposition may comprise sterile suspension bulk compounding and asepticfilling.

Other embodiments of the present materials are in the form of apolymeric drug delivery system that is capable of providing sustaineddrug delivery for extended periods of time after a singleadministration. For example, the present drug delivery systems canrelease the GD for at least about 1 month, or about 3 months, or about 6months, or about 1 year, or about 5 years or more. Thus, suchembodiments of the present materials may comprise a polymeric componentassociated with the therapeutic component in the form of a polymericdrug delivery system suitable for administration to a patient by atleast one of intravitreal administration and periocular administration.

The polymeric drug delivery system may be in the form of biodegradablepolymeric implants, non-biodegradable polymeric implants, biodegradablepolymeric microparticles, and combinations thereof. Implants may be inthe form of rods, wafers, sheets, filaments, spheres, and the like.Particles are generally smaller than the implants disclosed herein, andmay vary in shape. For example, certain embodiments of the presentinvention utilize substantially spherical particles. These particles maybe understood to be microspheres. Other embodiments may utilize randomlyconfigured particles, such as particles that have one or more flat orplanar surfaces. The drug delivery system may comprise a population ofsuch particles with a predetermined size distribution. For example, amajor portion of the population may comprise particles having a desireddiameter measurement.

As discussed herein, the polymeric component of the present drugdelivery systems can comprise a polymer selected from the groupconsisting of biodegradable polymers, non-biodegradable polymers,biodegradable copolymers, non-biodegradable copolymers, and combinationsthereof. In certain embodiments, the polymeric component comprises apoly (lactide-co-glycolide) polymer (PLGA). In other embodiments, thepolymeric component comprises a polymer selected from the groupconsisting of poly-lactic acid (PLA), poly-glycolic acid (PGA),poly-lactide-co-glycolide (PLGA), polyesters, poly (ortho ester),poly(phosphazine), poly (phosphate ester), polycaprolactones, gelatin,collagen, derivatives thereof, and combinations thereof. The polymericcomponent may be associated with the therapeutic component to form animplant selected from the group consisting of solid implants, semisolidimplants, and viscoelastic implants.

The GD may be in a particulate or powder form and entrapped by abiodegradable polymer matrix. Usually, GD particles in intraocularimplants will have an effective average size measuring less than about3000 nanometers. However, in other embodiments, the particles may havean average maximum size greater than about 3000 nanometers. In certainimplants, the particles may have an effective average particle sizeabout an order of magnitude smaller than 3000 nanometers. For example,the particles may have an effective average particle size of less thanabout 500 nanometers. In additional implants, the particles may have aneffective average particle size of less than about 400 nanometers, andin still further embodiments, a size less than about 200 nanometers. Inaddition, when such particles are combined with a polymeric component,the resulting polymeric intraocular particles may be used to provide adesired therapeutic effect.

If formulated as part of an implant or other drug delivery system, theGD of the present systems is preferably from about 1% to 90% by weightof the drug delivery system. More preferably, the GD is from about 20%to about 80% by weight of the system. In a preferred embodiment, the GDcomprises about 40% by weight of the system (e.g., 30%-50%). In anotherembodiment, the GD comprises about 60% by weight of the system.

Suitable polymeric materials or compositions for use in the drugdelivery systems include those materials which are compatible, that isbiocompatible, with the eye so as to cause no substantial interferencewith the functioning or physiology of the eye. Such materials preferablyinclude polymers that are at least partially and more preferablysubstantially completely biodegradable or bioerodible.

In addition to the foregoing, examples of useful polymeric materialsinclude, without limitation, such materials derived from and/orincluding organic esters and organic ethers, which when degraded resultin physiologically acceptable degradation products, including themonomers. Also, polymeric materials derived from and/or including,anhydrides, amides, orthoesters and the like, by themselves or incombination with other monomers, may also find use. The polymericmaterials may be addition or condensation polymers, advantageouslycondensation polymers. The polymeric materials may be cross-linked ornon-cross-linked, for example not more than lightly cross-linked, suchas less than about 5%, or less than about 1% of the polymeric materialbeing cross-linked. For the most part, besides carbon and hydrogen, thepolymers will include at least one of oxygen and nitrogen,advantageously oxygen. The oxygen may be present as oxy, e.g. hydroxy orether, carbonyl, e.g. non-oxo-carbonyl, such as carboxylic acid ester,and the like. The nitrogen may be present as amide, cyano and amino. Thepolymers set forth in Heller, Biodegradable Polymers in Controlled DrugDelivery, In: CRC Critical Reviews in Therapeutic Drug Carrier Systems,Vol. 1, CRC Press, Boca Raton, Fla. 1987, pp 39-90, which describesencapsulation for controlled drug delivery, may find use in the presentdrug delivery systems.

Of additional interest are polymers of hydroxyaliphatic carboxylicacids, either homopolymers or copolymers, and polysaccharides.Polyesters of interest include polymers of D-lactic acid, L-lactic acid,racemic lactic acid, glycolic acid, polycaprolactone, and combinationsthereof. Generally, by employing the L-lactate or D-lactate, a slowlyeroding polymer or polymeric material is achieved, while erosion issubstantially enhanced with the lactate racemate.

Among the useful polysaccharides are, without limitation, calciumalginate, and functionalized celluloses, particularlycarboxymethylcellulose esters characterized by being water insoluble, amolecular weight of about 5 kD to 500 kD, for example.

Other polymers of interest include, without limitation, polyesters,polyethers and combinations thereof which are biocompatible and may bebiodegradable and/or bioerodible.

Some preferred characteristics of the polymers or polymeric materialsfor use in the present systems may include biocompatibility,compatibility with the therapeutic component, ease of use of the polymerin making the drug delivery systems of the present invention, ahalf-life in the physiological environment of at least about 6 hours,preferably greater than about one day, not significantly increasing theviscosity of the vitreous, and water insolubility.

The biodegradable polymeric materials which are included to form thematrix are desirably subject to enzymatic or hydrolytic instability.Water soluble polymers may be cross-linked with hydrolytic orbiodegradable unstable cross-links to provide useful water insolublepolymers. The degree of stability can be varied widely, depending uponthe choice of monomer, whether a homopolymer or copolymer is employed,employing mixtures of polymers, and whether the polymer includesterminal acid groups.

Also important to controlling the biodegradation of the polymer andhence the extended release profile of the drug delivery systems is therelative average molecular weight of the polymeric composition employedin the present systems. Different molecular weights of the same ordifferent polymeric compositions may be included in the systems tomodulate the release profile. In certain systems, the relative averagemolecular weight of the polymer will range from about 9 to about 64 kD,usually from about 10 to about 54 kD, and more usually from about 12 toabout 45 kD.

In some drug delivery systems, copolymers of glycolic acid and lacticacid are used, where the rate of biodegradation is controlled by theratio of glycolic acid to lactic acid. The most rapidly degradedcopolymer has roughly equal amounts of glycolic acid and lactic acid.Homopolymers, or copolymers having ratios other than equal, are moreresistant to degradation. The ratio of glycolic acid to lactic acid willalso affect the brittleness of the system, where a more flexible systemor implant is desirable for larger geometries. The % of polylactic acidin the polylactic acid polyglycolic acid (PLGA) copolymer can be 0-100%,preferably about 15-85%, more preferably about 35-65%. In some systems,a 50/50 PLGA copolymer is used.

The biodegradable polymer matrix of the present systems may comprise amixture of two or more biodegradable polymers. For example, the systemmay comprise a mixture of a first biodegradable polymer and a differentsecond biodegradable polymer. One or more of the biodegradable polymersmay have terminal acid groups.

Release of a drug from an erodible polymer is the consequence of severalmechanisms or combinations of mechanisms. Some of these mechanismsinclude desorption from the implants surface, dissolution, diffusionthrough porous channels of the hydrated polymer and erosion. Erosion canbe bulk or surface or a combination of both. It may be understood thatthe polymeric component of the present systems is associated with thetherapeutic component so that the release of the therapeutic componentinto the eye is by one or more of diffusion, erosion, dissolution, andosmosis. As discussed herein, the matrix of an intraocular drug deliverysystem may release drug at a rate effective to sustain release of anamount of the GD for more than one week after implantation into an eye.In certain systems, therapeutic amounts of the GD are released for morethan about one month, and even for about twelve months or more. Forexample, the therapeutic component can be released into the eye for atime period from about ninety days to about one year after the system isplaced in the interior of an eye.

The release of the GD from the drug delivery systems comprising abiodegradable polymer matrix may include an initial burst of releasefollowed by a gradual increase in the amount of the GD released, or therelease may include an initial delay in release of the GD followed by anincrease in release. When the system is substantially completelydegraded, the percent of the GD that has been released is about onehundred.

It may be desirable to provide a relatively constant rate of release ofthe therapeutic agent from the drug delivery system over the life of thesystem. For example, it may be desirable for the GD to be released inamounts from about 0.01 μg to about 2 μg per day for the life of thesystem. However, the release rate may change to either increase ordecrease depending on the formulation of the biodegradable polymermatrix. In addition, the release profile of the GD may include one ormore linear portions and/or one or more non-linear portions. Preferably,the release rate is greater than zero once the system has begun todegrade or erode.

The drug delivery systems, such as the intraocular implants, may bemonolithic, i.e. having the active agent or agents homogenouslydistributed through the polymeric matrix, or encapsulated, where areservoir of active agent is encapsulated by the polymeric matrix. Dueto ease of manufacture, monolithic implants are usually preferred overencapsulated forms. However, the greater control afforded by theencapsulated, reservoir-type implant may be of benefit in somecircumstances, where the therapeutic level of the GD falls within anarrow window. In addition, the therapeutic component, including thetherapeutic agent(s) described herein, may be distributed in anon-homogenous pattern in the matrix. For example, the drug deliverysystem may include a portion that has a greater concentration of the GDrelative to a second portion of the system.

The polymeric implants disclosed herein may have a size of between about5 μm and about 2 mm, or between about 10 μm and about 1 mm foradministration with a needle, greater than 1 mm, or greater than 2 mm,such as 3 mm or up to 10 mm, for administration by surgicalimplantation. The vitreous chamber in humans is able to accommodaterelatively large implants of varying geometries, having lengths of, forexample, 1 to 10 mm. The implant may be a cylindrical pellet (e.g., rod)with dimensions of about 2 mm×0.75 mm diameter. Or the implant may be acylindrical pellet with a length of about 7 mm to about 10 mm, and adiameter of about 0.75 mm to about 1.5 mm.

The implants may also be at least somewhat flexible so as to facilitateboth insertion of the implant in the eye, such as in the vitreous, andaccommodation of the implant. The total weight of the implant is usuallyabout 250-5000 μg, more preferably about 500-1000 μg. For example, animplant may be about 500 μg, or about 1000 μg. However, larger implantsmay also be formed and further processed before administration to aneye. In addition, larger implants may be desirable where relativelygreater amounts of the GD are provided in the implant. For non-humanindividuals, the dimensions and total weight of the implant(s) may belarger or smaller, depending on the type of individual. For example,humans have a vitreous volume of approximately 3.8 ml, compared withapproximately 30 ml for horses, and approximately 60-100 ml forelephants. An implant sized for use in a human may be scaled up or downaccordingly for other animals, for example, about 8 times larger for animplant for a horse, or about, for example, 26 times larger for animplant for an elephant.

Drug delivery systems can be prepared where the center may be of onematerial and the surface may have one or more layers of the same or adifferent composition, where the layers may be cross-linked, or of adifferent molecular weight, different density or porosity, or the like.For example, where it is desirable to quickly release an initial bolusof GD, the center may be a polylactate coated with apolylactate-polyglycolate copolymer, so as to enhance the rate ofinitial degradation. Alternatively, the center may be polyvinyl alcoholcoated with polylactate, so that upon degradation of the polylactateexterior the center would dissolve and be rapidly washed out of the eye.

The drug delivery systems may be of any geometry including fibers,sheets, films, microspheres, spheres, circular discs, plaques and thelike. The upper limit for the system size will be determined by factorssuch as toleration for the system, size limitations on insertion, easeof handling, etc. Where sheets or films are employed, the sheets orfilms will be in the range of at least about 0.5 mm×0.5 mm, usuallyabout 3-10 mm×5-10 mm with a thickness of about 0.1-1.0 mm for ease ofhandling. Where fibers are employed, the fiber diameter will generallybe in the range of about 0.05 to 3 mm and the fiber length willgenerally be in the range of about 0.5-10 mm. Spheres may be in therange of about 0.5 μm to 4 mm in diameter, with comparable volumes forother shaped particles.

The size and form of the system can also be used to control the rate ofrelease, period of treatment, and drug concentration at the site ofimplantation. For example, larger implants will deliver aproportionately larger dose, but depending on the surface to mass ratio,may have a slower release rate. The particular size and geometry of thesystem are chosen to suit the site of implantation.

The proportions of GD-containing therapeutic agent, polymer, and anyother modifiers may be empirically determined by formulating severalimplants, for example, with varying proportions of such ingredients. AUSP approved method for dissolution or release test can be used tomeasure the rate of release (USP 23; NF 18 (1995) pp. 1790-1798). Forexample, using the infinite sink method, a weighed sample of the implantis added to a measured volume of a solution containing 0.9% NaCl inwater, where the solution volume will be such that the drugconcentration is after release is less than 5% of saturation. Themixture is maintained at 37° C. and stirred slowly to maintain theimplants in suspension. The appearance of the dissolved drug as afunction of time may be followed by various methods known in the art,such as by spectrophotometry, HPLC, mass spectroscopy, etc. until theabsorbance becomes constant or until greater than 90% of the drug hasbeen released.

In addition to the GD-containing therapeutic component, and similar tothe compositions described herein, the polymeric drug delivery systemsdisclosed herein may include an excipient component. The excipientcomponent may be understood to include solubilizing agents, viscosityinducing agents, buffer agents, tonicity agents, preservative agents,and the like.

Additionally, release modulators such as those described in U.S. Pat.No. 5,869,079 may be included in the drug delivery systems. The amountof release modulator employed will be dependent on the desired releaseprofile, the activity of the modulator, and on the release profile ofthe therapeutic agent in the absence of modulator. Electrolytes such assodium chloride and potassium chloride may also be included in thesystems. Where the buffering agent or enhancer is hydrophilic, it mayalso act as a release accelerator. Hydrophilic additives act to increasethe release rates through faster dissolution of the material surroundingthe drug particles, which increases the surface area of the drugexposed, thereby increasing the rate of drug bioerosion. Similarly, ahydrophobic buffering agent or enhancer dissolve more slowly, slowingthe exposure of drug particles, and thereby slowing the rate of drugbioerosion.

Various techniques may be employed to produce such drug deliverysystems. Useful techniques include, but are not necessarily limited to,solvent evaporation methods, phase separation methods, interfacialmethods, molding methods, injection molding methods, extrusion methods,co-extrusion methods, carver press method, die cutting methods, heatcompression, combinations thereof and the like.

Specific methods are discussed in U.S. Pat. No. 4,997,652. Extrusionmethods may be used to avoid the need for solvents in manufacturing.When using extrusion methods, the polymer and drug are chosen so as tobe stable at the temperatures required for manufacturing, usually atleast about 85 degrees Celsius. Extrusion methods use temperatures ofabout 25 degrees C. to about 150 degrees C., more preferably about 65degrees C. to about 130 degrees C. An implant may be produced bybringing the temperature to about 60 degrees C. to about 150 degrees C.for drug/polymer mixing, such as about 130 degrees C., for a time periodof about 0 to 1 hour, 0 to 30 minutes, or 5-15 minutes. For example, atime period may be about 10 minutes, preferably about 0 to 5 min. Theimplants are then extruded at a temperature of about 60 degrees C. toabout 130 degrees C., such as about 75 degrees C.

In addition, the implant may be coextruded so that a coating is formedover a core region during the manufacture of the implant.

Compression methods may be used to make the drug delivery systems, andtypically yield elements with faster release rates than extrusionmethods. Compression methods may use pressures of about 50-150 psi, morepreferably about 70-80 psi, even more preferably about 76 psi, and usetemperatures of about 0 degrees C. to about 115 degrees C., morepreferably about 25 degrees C.

In certain embodiments of the present invention, a method of producing asustained-release intraocular drug delivery system, comprises combiningan GD and a polymeric material to form a drug delivery system suitablefor placement in an eye of an individual. The resulting drug deliverysystem is effective in releasing the GD into the eye for extendedperiods of time. The method may comprise a step of extruding aparticulate mixture of the GD and the polymeric material to form anextruded composition, such as a filament, sheet, and the like.

When polymeric particles are desired, the method may comprise formingthe extruded composition into a population of polymeric particles or apopulation of implants, as described herein. Such methods may includeone or more steps of cutting the extruded composition, milling theextruded composition, and the like.

As discussed herein, the polymeric material may comprise a biodegradablepolymer, a non-biodegradable polymer, or a combination thereof. Examplesof polymers include each and every one of the polymers and agentsidentified above.

Embodiments of the present invention also relate to compositionscomprising the present drug delivery systems. For example, and in oneembodiment, a composition may comprise the present drug delivery systemand an ophthalmically acceptable carrier component. Such a carriercomponent may be an aqueous composition, for example saline or aphosphate buffered liquid.

Another embodiment relates to a method of producing an ophthalmicallytherapeutic material which comprises an GD. In a broad aspect, themethod comprises the steps of selecting an GD and combining the selectedGD with a liquid carrier component or a polymeric component to form amaterial suitable for administration to an eye. Or stated differently, amethod of producing the present materials may comprise a step ofselecting GDs having a low aqueous humor/vitreous humor concentrationratio and long intravitreal half-life.

The method may further comprise one or more of the following steps,which will typically be used to select the GD: administering an GD to aneye of a subject and determining the concentration of the GD in at leastone of the vitreous humor and aqueous humor as a function of time; andadministering a GD to an eye of a subject and determining at least oneof the vitreous half-life and clearance of the GD from the posteriorchamber of the eye.

The material formed in the method may be a liquid-containingcomposition, a biodegradable polymeric implant, a non-biodegradablepolymeric implant, polymeric microparticles, or combinations thereof. Asdiscussed herein, the material may be in the form of solid implants,semisolid implants, and viscoelastic implants. In certain embodiments,the GD is combined with a polymeric component to form a mixture, and themethod further comprises extruding the mixture.

Additional embodiments of the present invention related to methods ofimproving or maintaining vision of an eye of a patient. In general, themethods comprise a step of administering the present ophthalmicallytherapeutic material to an eye of an individual in need thereof.Administration, such as intravitreal or periocular (or less preferably,topical) administration of the present materials can be effective intreating posterior ocular conditions without significantly affecting theanterior chamber. The present materials may be particularly useful intreating inflammation and edema of the retina. Administration of thepresent materials are effective in delivering the GD to one or moreposterior structures of the eye including the uveal tract, the vitreous,the retina, the choroid, the retinal pigment epithelium.

When a syringe apparatus is used to administer the present materials,the apparatus can include an appropriately sized needle, for example, a27-gauge needle or a 30-gauge needle. Such apparatus can be effectivelyused to inject the materials into the posterior segment or a periocularregion of an eye of a human or animal. The needles may be sufficientlysmall to provide an opening that self seals after removal of the needle.

The present methods may comprise a single injection into the posteriorsegment of an eye or may involve repeated injections, for example overperiods of time ranging from about one week or about 1 month or about 3months to about 6 months or about 1 year or longer.

The present materials are preferably administered to patients in asterile form. For example, the present materials may be sterile whenstored. Any routine suitable method of sterilization may be employed tosterilize the materials. For example, the present materials may besterilized using radiation. Preferably, the sterilization method doesnot reduce the activity or biological or therapeutic activity of thetherapeutic agents of the present systems.

The materials can be sterilized by gamma irradiation. As an example, thedrug delivery systems can be sterilized by 2.5 to 4.0 mrad of gammairradiation. The drug delivery systems can be terminally sterilized intheir final primary packaging system including administration devicee.g. syringe applicator. Alternatively, the drug delivery systems can besterilized alone and then aseptically packaged into an applicatorsystem. In this case the applicator system can be sterilized by gammairradiation, ethylene oxide (ETO), heat or other means. The drugdelivery systems can be sterilized by gamma irradiation at lowtemperatures to improve stability or blanketed with argon, nitrogen orother means to remove oxygen. Beta irradiation or e-beam may also beused to sterilize the implants as well as UV irradiation. The dose ofirradiation from any source can be lowered depending on the initialbioburden of the drug delivery systems such that it may be much lessthan 2.5 to 4.0 mrad. The drug delivery systems may be manufacturedunder aseptic conditions from sterile starting components. The startingcomponents may be sterilized by heat, irradiation (gamma, beta, UV), ETOor sterile filtration. Semi-solid polymers or solutions of polymers maybe sterilized prior to drug delivery system fabrication and GDincorporation by sterile filtration of heat. The sterilized polymers canthen be used to aseptically produce sterile drug delivery systems.

In another aspect of the invention, kits for treating an ocularcondition of the eye are provided, comprising: a) a container, such as asyringe or other applicator, comprising an GD as herein described; andb) instructions for use. Instructions may include steps of how to handlethe material, how to insert the material into an ocular region, and whatto expect from using the material. The container may contain a singledose of the GD.

EXAMPLES Example 1

Recombinant vascular endothelial growth factor (VEGF) was obtained froma supplier (R&D Systems). Female Dutch Belt rabbits were anaesthetizedwith isoflurane inhalation and topical 0.5% proparacaine hydrochloride,and intravitreal injection of one eye with 500 ng VEGF in sterilephosphate buffered saline (PBS) containing 0.1% bovine serum albumin wasperformed using a 28 guage ½ inch needle. The other eye is given thesame volume of the vehicle, without the VEGF.

The extent of VEGF-induced BRB and BAB breakdown of the blood retinalbarrier and the blood aqueous barrier was measured by scanning ocularfluorophotemetry (Fluorotron Master, Ocumetrics Inc.); at various timesfollowing intravitreal injection. In this model a fluorescent label isadministered intravenously, following by determination of the amount offluorescenin in the anterior and posterior segment and an indication ofiridial and retinal leakage, respectively.

Under normal conditions the blood retinal and blood aqueous barrierprevents solutes in the blood from infiltrating the vitreous (and to asomewhat lesser but very significant extent, the aqueous). By contrast,in the presence of retinal disease such as macular degeneration,retinopathy, macular edema, retinal neovascularization etc., there isleakage of blood into retinal tissue, and the fluorescent tracer will bevisible in the vitreous and aqueous of the eye. VEGF injection mimicsthis pathological condition.

FIG. 2 shows representative traces of fluorescein leakage (arbitraryfluorescence units) from rabbit retina and iris from a single eye twodays (48 hours) after intravitreal VEGF injection. Sodium fluorescein in1 ml saline was injected via the marginal ear vein at a concentration of50 mg/kg, and ocular fluorescein levels in the vitreoretinal chamber andthe anterior chamber was determined 50 minutes later.

Compared to normal untreated rabbit eyes, VEGF caused an approximately18-fold increase in fluorescein contained in the vitreous, and anapproximately 6-fold increase in fluorescein contained in the aqueous,which reflects breakdown in the blood retinal barrier (BRB) causingretinal leakage, and the blood aqueous barrier (BAB) iris leakage),respectively.

Both of these responses were completely blocked by the corticosteroidsdexamethasone, triamcinolone and beclomethasone, when thesecorticosteroids were either administered systemically or intravitreally.See infra and Edelman et al., EXP. EYE RES. 80:249-258 (2005),incorporated by reference herein. Thus, when, after steroid treatment,both the anterior and posterior chambers are free of fluorescein leakagefollowing VEGF challenge, this indicates that the steroid is able toinfiltrate both chambers effectively.

Five corticosteroids (dexamethasone, triamcinolone, fluticasonepropionate, beclomethasone dipropionate and beclomethasone) werepurchased from Sigma-Aldrich Co. and evaluated in this model system. Incombination these compounds define a solubility range of nearly threelog units (1000 fold) from the most water soluble to the least watersoluble, and a range of lipophilicity coefficients, log P, from 1.95 to4.4.

Ten milligrams of each compound is added to 1 ml of sterilephosphate-buffered saline (PBS; ph 7.4). At day 0, 100 ml of a 10 mg/mlsuspension of each steroid is injected into the vitreous of a rabbiteye. The PBS vehicle is injected into the other eye. VEGF is theninjected at a pre-determined time (one month) thereafter, and BRB andBAB breakdown were measured by scanning ocular fluorophotometry 48 hrslater as described in Edelman et al., EXP. EYE RES. 80:249-258 (2005),hereby incorporated by reference herein in its entirety.

Compound Water Solubility Lipophicity (log P) Dexamethasone 100 mg/ml1.95 (Sigma cat. # D1756) Triamcinolone 21.0 mg/ml 2.53 acetonide (Sigmacat. # T6501) Fluticasone 0.14 mg/ml 4.20 propionate (Sigma cat. #F9428) Beclomethasone 0.13 mg/ml 4.40 dipropionate (Sigma cat. # B3022)

As can be seen, of the compounds tested dexamethasone (DEX) had thehighest water solubility (100 mg/ml) and lowest lipophilicity (logP=1.95) of the five compounds tested. After intravitreal injection of 1mg crystalline dexamethasone suspended in 100 μL PBS, dexamethasonecompletely inhibited VEGF-induced leakage of intravenous fluoresceininto both the posterior segment and the anterior segment, indicatingthat intravitreally administered dexamethasone is present in bothposterior and anterior segments to inhibit BRB and BAB breakdown,respectively (FIG. 3). Since the BAB is normally relatively leakycompared to the BRB (see FIG. 1), there is some residual fluorescenceobserved in the anterior chamber of rabbit eyes treated withdexamethasone.

This result indicated that intravitreally administered dexamethasonereadily diffuses from the crystal depot within the vitreous in bothdirections: in the posterior direction to the retinal vasculature and inthe anterior direction to the iris. These characteristics result inpharmacologically active levels within both tissues.

Similar to the result with dexamethasone, 1 mg of triamcinoloneacetonide contained in 100 μL of an aqueous suspension and injected intothe vitreous also completely inhibited VEGF-stimulated BRB and BABbreakdown (FIG. 4).

As a final example of the effect of unsubstituted glucocorticoids, 100μl of a 10 mg/ml suspension of aqueous beclomethasone was injected intothe vitreous of a rabbit eye, followed by VEGF as described above. Aswith dexamethasone and triamcinolone, beclomethasone inhibited theVEGF-induced breakdown of the BRB and the BAB (FIG. 5).

In contrast, intravitreal injection of rabbit eye with 100 μl of a 10mg/ml suspension of fluticasone propionate (water solubility 0.14 mg/ml;log P=4.2), followed by intravitreal administration of VEGF, completelyblocked BRB breakdown but had no effect on BAB breakdown (FIG. 6). Thisresult indicates that the intravitreally placed drug is able to diffusein therapeutically effective concentrations from the vitreousposteriorly to the retina, but is unable to diffuse from the posteriorchamber to the anterior chamber in such concentration.

Similarly, another sparingly water soluble compound, beclomethasone17,21-dipropionate (0.13 mg/ml; log P=4.4), appears to completely blockVEGF-induced BRB breakdown, but has no effect on BAB breakdown (FIG. 7).Moreover, 100 μl of 10 mg/ml intravitreal beclomethasone17,21-dipropionate completely inhibited VEGF-mediated responses forgreater than 3 months.

These results indicate that GDs that possessing one or more hydrophobicC₁₇ and/or C₂₁ substitution (in this case, an acyl monoester functionalgroup, such as propionate) have reduced water solubility, increasedlipophilicity, and are superior pharmacophores for intravitreal deliveryto treat ocular diseases that largely or solely involve the posteriorsegment or have little or no anterior chamber components. Intravitrealadministration of these compounds therefore display few, reduced, orabrogated anterior segment side effects such as cataracts, high IOP, andsteroid inducted glaucoma. Specific examples of these compounds includedexamethasone 17-acetate, dexamethasone 17, 21-acetate, dexamethasone21-acetate, clobetasone 17-butyrate, beclomethasone 17, 21-dipropionate,fluticasone 17-propionate, clobetasol 17-propionate, betamethasone 17,21-dipropionate, alclometasone 17,21-dipropionate, dexamethasone17,21-dipropionate, dexamethasone 17-propionate, halobetasol17-propionate, betamethasone 17-valerate. These compounds will be asignificant improvement compared to existing therapies in the treatmentof posterior eye diseases including, without limitation, dry and wetARMD, diabetic macular edema, proliferate diabetic retinopathy, uveitis,and ocular tumors.

Example 2 GD Implant

Biodegradable drug delivery systems can be made by combining a GD with abiodegradable polymer composition in a stainless steel mortar. Thecombination is mixed via a Turbula shaker set at 96 RPM for 15 minutes.The powder blend is scraped off the wall of the mortar and then remixedfor an additional 15 minutes. The mixed powder blend is heated to asemi-molten state at specified temperature for a total of 30 minutes,forming a polymer/drug melt.

Rods are manufactured by pelletizing the polymer/drug melt using a 9gauge polytetrafluoroethylene (PTFE) tubing, loading the pellet into thebarrel and extruding the material at the specified core extrusiontemperature into filaments. The filaments are then cut into about 1 mgsize implants or drug delivery systems. The rods have dimensions ofabout 2 mm long×0.72 mm diameter. The rod implants weigh between about900 μg and 1100 μg.

Wafers are formed by flattening the polymer melt with a Carver press ata specified temperature and cutting the flattened material into wafers,each weighing about 1 mg. The wafers have a diameter of about 2.5 mm anda thickness of about 0.13 mm. The wafer implants weigh between about 900μg and 1100 μg.

In-vitro release testing can be performed on each lot of implant (rod orwafer). Each implant may be placed into a 24 mL screw cap vial with 10mL of Phosphate Buffered Saline solution at 37° C. and 1 mL aliquots areremoved and replaced with equal volume of fresh medium on day 1, 4, 7,14, 28, and every two weeks thereafter.

Drug assays may be performed by HPLC, which consists of a Waters 2690Separation Module (or 2696), and a Waters 2996 Photodiode ArrayDetector. An Ultrasphere, C-18 (2), 5 □m; 4.6×150 mm column heated at30° C. can be used for separation and the detector can be set at 264 nm.The mobile phase can be (10:90) MeOH-buffered mobile phase with a flowrate of 1 mL/min and a total run time of 12 min per sample. The bufferedmobile phase may comprise (68:0.75:0.25:31) 13 mM 1-Heptane SulfonicAcid, sodium salt—glacial acetic acid—triethylamine—Methanol. Therelease rates can be determined by calculating the amount of drug beingreleased in a given volume of medium over time in □g/day.

The polymers chosen for the implants can be obtained from BoehringerIngelheim or Purac America, for example. Examples of polymers include:RG502, RG752, R202H, R203 and R206, and Purac PDLG (50/50). RG502 is(50:50) poly(D,L-lactide-co-glycolide), RG752 is (75:25)poly(D,L-lactide-co-glycolide), R202H is 100% poly(D, L-lactide) withacid end group or terminal acid groups, R203 and R206 are both 100%poly(D, L-lactide). Purac PDLG (50/50) is (50:50)poly(D,L-lactide-co-glycolide). The inherent viscosity of RG502, RG752,R202H, R203, R206, and Purac PDLG are 0.2, 0.2, 0.2, 0.3, 1.0, and 0.2dL/g, respectively. The average molecular weight of RG502, RG752, R202H,R203, R206, and Purac PDLG are, 11700, 11200, 6500, 14000, 63300, and9700 daltons, respectively.

Example 3 Manufacture of Double Extrusion GD Implant

Double extrusion methods may also be used for the manufacture of GDimplants. Such implants can be made as follows, and as set forth in asset forth in U.S. patent application Ser. No. 10/918,597, herebyincorporated by reference herein.

Thirty grams of RG502 were milled using the Jet-Mill (a vibratoryfeeder) at milling pressures of 60 psi, 80 psi and 80 psi for the pushernozzle, grinding nozzle, and grinding nozzle, respectively. Next, 60grams of RG502H were milled using the Jet-Mill at milling pressure of 20psi, 40 psi and 40 psi for the pusher nozzle, grinding nozzle, andgrinding nozzle, respectively. The mean particle size of both RG502 andRG502H is measured using a TSI 3225 Aerosizer DSP Particle SizeAnalyzer. Both milled polymers have a mean particle size of no greaterthan 20 um.

(b) Blending of GD and PLGA

48 grams of beclamethasone diproprionate (“DP”), 24 grams of milledRG502H and 8 grams of milled RG502 are blended using the Turbula Shakerset at 96 RPM for 60 minutes. For the first extrusion, all 80 grams ofthe blended DP/RG502H/RG502 mixture are added to the hopper of a HaakeTwin Screw Extruder. The Haake extruder is then turned on and thefollowing parameters are set:

-   Barrel Temperature: 105 degrees C.-   Nozzle Temperature: 102 degrees C.-   Screw Speed: 120 RPM-   Feed Rate Setting: 250-   Guide Plate Temperature: 50-55 degrees C.-   Circulating water bath: 10 degrees C.

The extruded filament is collected. The first filament begins extrudingabout 15-25 minutes after the addition of the powder blend. Thefilaments extruded in the first five minutes at these settings arediscarded. The remaining filaments are collected until exhaustion ofextrudates; this normally takes from 3 to 5 hours.

The resulting filaments are pelletized using the Turbula Shaker and one19 mm stainless steel ball set at 96 RPM for 5 minutes.

In the second extrusion all the pellets from the last step are addedinto the same hopper and the Haake extruder turned on.

-   The extruder is set as follows:-   Barrel Temperature: 107° C.-   Nozzle temperature: 90° C.-   Screw speed: 100 RPM-   Guide Plate Temperature: 60-65° C.-   Circulation water bath: 10° C.

All extruded filaments are collected until exhaustion of extrudates.This normally takes about 3 hours. The bulk filaments are cut to anappropriate length to give the desired dosage strengths, for example 350μg and 700 μg. The single and double extruded implants have thecharacteristics shown by the following Tables 1 and 2, respectively.

TABLE 1 In Process Controls for the First Extrusion Batch Number 03J00103H004 03M001 Batch size Parameter Specifications 80 g 80 g 80 gFilament 0.85 to 1.14 g/cm³ 1.03 1.01 1.04 density Uniformity 85.0 to115.0%⁽¹⁾ 99.3 100.5 98.7 Potency 97.0 to 103.0% label 100.1 100.0 99.8strength Degradation ≤1.5% total 0.2 0.2 0.2 products ≤0.75% acid ND NDND ≤0.75% ketone ≤0.08 ≤0.10 ≤0.13 ≤0.75% aldehyde ≤0.15 ≤0.10 ≤0.12⁽¹⁾Percentage of target weight

TABLE 2 In Process Controls for the second extrusion Batch number 03J00103H004 03M001 Batch size Parameter Specifications 80 g 80 g 80 gAppearance White to off white pass pass pass Filament density 1.10 to1.30 g/cm³ 1.18 1.13 1.19 Diameter ≤80% within 0.0175 to 0.0185 inch 100100 100 Fracture force ≤2 g 9.88 9.39 9.52 Fracture energy ≤0.9 μJ 5.884.54 4.64 Moisture ≥1.0% 0.4 0.4 0.4 Foreign No visible foreignmaterials Pass Pass Pass particulate Insoluble mater Particle count (forinformation Diameter ≤ 10 μm 17 26 2.6 only) Diameter ≤ 25 μm 0.5 1 0 GDidentity Positive for GD positive positive positive Potency 95.0 to105.0% label strength 98.5 101.2 99.9 Degradation ≤2% total 1.1 0.6 1.0products ≤0.5% acid ND ND ND ≤1.0% ketone 0.4 0.2 0.4 ≤1.0% aldehyde 0.70.4 0.5 GD release Pass Pass Pass Uniformity 85.0-115.0% Label Strength(LS) 97.0% 97.1% 98.0% Stage 1 (n = 10): If one unit is outside allvalues all all values the range and between 75% and within values within125% LS or RSD ≥ 6.0%, test range within range 20 more units. rangeStage 2 (n = 20): pass if no more than 1 unit is outside the range, andis between 75% and 125% LS, and the RSD ≤ 7.8%.

Example 4 Treatment of Macular Edema with a GD Implant

A 58 year old man diagnosed with cystic macular edema treated byadministration of a biodegradable drug delivery system administered toeach eye of the patient. A 2 mg intravitreal implant containing about1000 μg of PLGA and about 1000 μg of beclomethasone dipropionate isplaced in his left eye at a location that does not interfere with theman's vision. A similar implant is administered subconjunctivally to thepatient's right eye. A more rapid reduction in retinal thickness in theright eye appears to be due to the location of the implant and theactivity of the steroid. After about 3 months from the surgery, theman's retinal appears normal, and degeneration of the optic nerveappears to be reduced. No increase in intraocular pressure is seen oneweek after administration.

Example 5 Treatment of ARMD with a GD Composition

A 62 year old woman with wet age-related macular degeneration is treatedwith an intravitreal injection of 100 μl of a hyaluronic acid solutioncontaining about 1000 μg of fluticasone propionate crystals insuspension. Within one month following administration the patientexhibits an acceptable reduction in the rate of neovascularization andrelated inflammation. The patient reports an overall improvement inquality of life.

All references, articles, publications and patents and patentapplications cited herein are incorporated by reference in theirentireties.

While this invention has been described with respect to various specificexamples and embodiments, it is to be understood that the invention isnot limited thereto and that it can be variously practiced within thescope of the following claims.

What is claimed is:
 1. An ophthalmic composition comprising: atherapeutically effective amount of a Glucocorticoid Derivative (GD)comprising an acyl group linked to C₁₇, C₂₁, or combination thereof viaan ester linkage, and a viscosity-inducing component.
 2. The compositionof claim 1 wherein said GD has a lipophilicity greater than 2.53.
 3. Thecomposition of claim 1 wherein said GD has an aqueous solubility lessthan 10 mg/ml.
 4. The composition of claim 1, wherein theviscosity-inducing component comprises hyaluronic acid, carbomers,polyacrylic acid, cellulosic derivatives, polycarbophil,polyvinylpyrrolidone, gelatin, dextrin, polysaccharides, polyacrylamide,polyvinyl alcohol, polyvinyl acetate, derivatives thereof and mixturesthereof.
 5. The composition of claim 4, wherein the viscosity-inducingcomponent comprises a polymeric hyaluronate component.
 6. Thecomposition of claim 1 wherein said acyl group is selected from thegroup consisting of an acetyl, butyryl, valeryl, propionyl, furoyl, andbenzoyl group.
 7. The composition of claim 1 wherein said composition issuitable for administration to a patient by at least one of intravitrealadministration and periocular administration.
 8. The composition ofclaim 1 wherein said ophthalmic composition is an implant.
 9. Thecomposition of claim 8 wherein said implant further comprises apolymeric component.
 10. The composition of claim 9 wherein saidpolymeric component is selected from the group consisting of poly(lactide-co-glycolide) polymer (PLGA), poly-lactic acid (PLA),poly-glycolic acid (PGA), polyesters, poly (ortho ester),poly(phosphazine), poly (phosphate ester), polycaprolactones, gelatin,and collagen, and derivatives and combinations thereof.
 11. Thecomposition of claim 1, wherein the GD is beclomethasone propionate. 12.The composition of claim 1, wherein the GD is beclomethasonedipropionate.